risdiplam | 1825352-65-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: risdiplam
• 英文别名: 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one；RG7916；Risdiplam
• CAS: 1825352-65-5
• 化学式: C₂₂H₂₃N₇O
• 分子量: 401.471
• InChiKey: ASKZRYGFUPSJPN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  30
• 可旋转键数：
  2
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  78.1
• 氢给体数：
  1
• 氢受体数：
  6

ADMET

代谢

利司扑兰的代谢主要由黄素单加氧酶1和3（FMO1和FMO3）介导，CYP1A1、CYP2J2、CYP3A4和CYP3A7也有所参与。母药大约占循环药物材料的83%。已确定一种药理学上不活跃的代谢物M1是主要的循环代谢物——这种M1代谢物在体外实验中被观察到能够抑制MATE1和MATE2-K转运体，类似于母药。

The metabolism of risdiplam is mediated primarily by flavin monooxygenases 1 and 3 (FMO1 and FMO3), with some involvement of CYP1A1, CYP2J2, CYP3A4, and CYP3A7. Parent drug comprises approximately 83% of circulating drug material. A pharmacologically-inactive metabolite, M1, has been identified as the major circulating metabolite - this M1 metabolite has been observed _in vitro_ to inhibit MATE1 and MATE2-K transporters, similar to the parent drug.

来源:DrugBank

毒理性

• 毒性总结

关于利司普兰过量的数据不可用。过量的症状可能与利司普兰的不良反应特征一致，因此可能包括高烧、腹泻和皮肤反应。

Data regarding overdose of risdiplam are unavailable. Symptoms of overdose are likely to be consistent with risdiplam's adverse effect profile, and may therefore involve significant fever, diarrhea, and skin reactions.

来源:DrugBank

毒理性

• 蛋白质结合

利司哌兰在大约89%的血浆中与蛋白结合，主要是与血清白蛋白结合。

Risdiplam is approximately 89% protein-bound in plasma, primarily to serum albumin.

来源:DrugBank

吸收、分配和排泄

• 吸收

口服给药后的Tmax大约在1-4小时。每日一次随早餐服用（或哺乳后），利司普兰在大约7-14天内达到稳态。在SMA患者中，利司普兰的药代动力学在所有研究剂量之间大约呈线性关系。

The T_max following oral administration is approximately 1-4 hours. Following once-daily administration with a morning meal (or after breastfeeding), risdiplam reaches steady-state in approximately 7-14 days. The pharmacokinetics of risdiplam were found to be approximately linear between all studied dosages in patients with SMA.

来源:DrugBank

吸收、分配和排泄

• 消除途径

口服18毫克利司迪帕后，约53%的剂量通过粪便排出，28%通过尿液排出。未改变的母药占粪便排出剂量的14%，占尿液排出剂量的8%。

Following the oral administration of 18mg risdiplam, approximately 53% of the dose was excreted in the feces and 28% was excreted in the urine. Unchanged parent drug comprised 14% of the dose excreted in feces and 8% of the dose excreted in urine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

经口服给药后，利司扑兰（risdiplam）在中央神经系统及周围组织中分布良好。稳态表观分布容积为6.3 L/kg。

Following oral administration, risdiplam distributes well into the central nervous system and peripheral tissues. The apparent volume of distribution at steady-state is 6.3 L/kg.

来源:DrugBank

吸收、分配和排泄

• 清除

对于一名14.9公斤的患者，利司扑兰的表观清除率为6.3升/公斤。

For a 14.9kg patient, the apparent clearance of risdiplam is 6.3 L/kg.

来源:DrugBank

反应信息

• 作为反应物：
  描述：

  酒石酸 、 risdiplam 以 水 为溶剂， 以92.8 %的产率得到7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one tartaric acid salt
  参考文献：
  名称：

  [EN] A NOVEL PROCESS FOR THE PREPARATION OF 7 (4, 7- DIAZASPIRO [2.5] OCTAN-7-YL)-2-(2,8 DIMETHYLIMIDAZO[1,2-B] PYRID AZIN-6- YL) PYRIDO-4H-[1,2-A] PYRIMIDIN-4-ONE WITH NOVEL INTERMEDIATES
  [FR] NOUVEAU PROCESSUS DE PRÉPARATION DE 7-(4,7-DIAZASPIRO[2,5]OCTANE-7-YL)-2-(2,8 DIMÉTHYLIMIDAZO[1,2-B]PYRIDAZINE-6-YL)PYRIDO-4H-[1,2-A]PYRIMIDINE-4-ONE AVEC DE NOUVEAUX INTERMÉDIAIRES

  摘要：

  The present invention relates to a process for the preparation of 7-(4,7-diazaspiro [2.5] octan- 7-yl)-2-(2,8-dimethylimidazo[l,2-b] pyridazin-6-yl) pyrido-4H-[1,2-a] pyrimidin-4-one represented by the following structural formula (1) by employing novel intermediates of formulae (5), (6), (7), (9) and (13). (1) The present invention further relates to process for the purification of 7-(4,7-diazaspiro [2.5] octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b] pyridazin-6-yl) pyrido-4H-[1,2-a] pyrimidin-4-one (1), is with purity greater than 99.5% by High-performance liquid chromatography.

  公开号：

  WO2024003798A1
• 作为产物：
  描述：

  3,6-二氯-4-甲基哒嗪 在 ammonium hydroxide 、 四(三苯基膦)钯 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 potassium acetate 、 potassium carbonate 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 水 、 二甲基亚砜 、 异丙醇 、 乙腈 为溶剂， 反应 117.0h， 生成 risdiplam
  参考文献：
  名称：

  [EN] COMPOSITIONS FOR TREATING SPINAL MUSCULAR ATROPHY
  [FR] COMPOSITIONS POUR LE TRAITEMENT D'UNE AMYOTROPHIE SPINALE

  摘要：

  本发明提供了包含式(I)化合物的药物组合物，其中A、R1、R2和R3如本文所述，并且其药学上可接受的盐。此外，本发明涉及制备包含式(I)化合物的药物组合物以及它们作为药物的用途。

  公开号：

  WO2017080967A1

文献信息

• [EN] PROCESS FOR THE PREPRATION OF 7-(4,7-DIAZASPIRO[2.5]OCTAN-7-YL)-2-(2,8-DIMETHYLIMIDAZO[1,2-B]PYRIDAZIN-6-YL)PYRIDO[1,2-A]PYRIMIDIN-4-ONE DERIVATIVES<br/>[FR] PROCÉDÉ DE PRÉPARATION DE DÉRIVÉS DE 7-(4,7-DIAZASPIRO[2.5]OCTAN-7-YL)-2-(2,8-DIMÉTHYLIMIDAZO[1,2-B]PYRIDAZIN-6-YL)PYRIDO[1,2-A]PYRIMIDIN-4-ONE
  申请人：HOFFMANN LA ROCHE

  公开号：WO2019057740A1

  公开（公告）日：2019-03-28

  The present invention relates to a process for the preparation of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[l,2- b]pyridazin-6-yl)pyrido[l,2-a]pyrimidin-4-one derivatives useful pharmaceutically active compounds.

  本发明涉及一种制备7-(4,7-二氮杂螺[2.5]辛烷-7-基)-2-(2,8-二甲基咪唑并[1,2-b]吡啶并[1,2-a]嘧啶-4-酮衍生物的方法，这些衍生物是有药用活性的化合物。
• [EN] COMPOUNDS FOR TREATING SPINAL MUSCULAR ATROPHY<br/>[FR] COMPOSÉS POUR LE TRAITEMENT D'UNE AMYOTROPHIE SPINALE
  申请人：HOFFMANN LA ROCHE

  公开号：WO2015173181A1

  公开（公告）日：2015-11-19

  The present invention provides compounds of formula (I) wherein A, R1, R2 and R3 are as described herein, as well as pharmaceutically acceptable salts thereof. Further the present invention is concerned with the manufacture of the compounds of formula (I), pharmaceutical compositions comprising them and their use as medicaments.

  本发明提供了式（I）的化合物，其中A、R1、R2和R3如本文所述，以及其药用可接受的盐。此外，本发明涉及制备式（I）的化合物、包含它们的药物组合物以及它们作为药物的用途。
• [EN] COMPOUNDS FOR TREATING AMYOTROPHIC LATERAL SCLEROSIS<br/>[FR] COMPOSÉS POUR LE TRAITEMENT DE LA SCLÉROSE LATÉRALE AMYOTROPHIQUE
  申请人：HOFFMANN LA ROCHE

  公开号：WO2017081111A1

  公开（公告）日：2017-05-18

  The present invention provides compounds of formula (I) (I) wherein A, R1, R2 and R3 are as described herein, as well as pharmaceutically acceptable salts thereof for use in the treatment, prevention and/or delay of progression of amyotrophic lateral sclerosis (ALS). Further the present invention is concerned with the manufacture of the compounds of formula (I), pharmaceutical compositions comprising them and their use as medicaments.

  本发明提供了如下式（I）的化合物（I）其中A、R1、R2和R3如本文所述，以及其在治疗、预防和/或延缓肌萎缩侧索硬化症（ALS）进展方面的药用盐。此外，本发明涉及如何制造如上式（I）的化合物、包含它们的药物组合物以及它们作为药物的用途。
• COMPOUNDS FOR TREATING SPINAL MUSCULAR ATROPHY
  申请人：Hoffmann-La Roche Inc.

  公开号：US20190315773A1

  公开（公告）日：2019-10-17

  The present invention provides compounds of formula (I) wherein A, R 1 , R 2 and R 3 are as described herein, as well as pharmaceutically acceptable salts thereof. Further the present invention is concerned with the manufacture of the compounds of formula (I), pharmaceutical compositions comprising them and their use as medicaments.

  本发明提供了以下式（I）的化合物，其中A、R1、R2和R3如本文所述，并且其药学上可接受的盐。此外，本发明涉及制备上述式（I）化合物，包括它们的药物组合物以及它们作为药物的用途。
• [EN] COMPOSITIONS FOR TREATING SPINAL MUSCULAR ATROPHY<br/>[FR] COMPOSITIONS POUR LE TRAITEMENT D'UNE AMYOTROPHIE SPINALE
  申请人：HOFFMANN LA ROCHE

  公开号：WO2017080967A1

  公开（公告）日：2017-05-18

  The present invention provides pharmaceutical compositions comprising a compound of formula (I) wherein A, R1, R2 and R3 are as described herein, as well as pharmaceutically acceptable salts thereof. Further the present invention is concerned with the manufacture of the pharmaceutical compositions comprising a compound of formula (I) and their use as medicaments.

  本发明提供了包含式(I)化合物的药物组合物，其中A、R1、R2和R3如本文所述，并且其药学上可接受的盐。此外，本发明涉及制备包含式(I)化合物的药物组合物以及它们作为药物的用途。